E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The overall study objective is to assess the safety, immunogenicity and efficacy of repeated doses of ACI-24 at 4 different dose levels administered to patients with mild to moderate Alzheimer’s disease (AD) patients. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial are to explore:
- the efficacy of ACI-24 in reducing Aβ level in the brain of patients with mild to moderate Alzheimer's disease
− the effect of ACI-24 on whole brain and hippocampal volume (for Step 2 only)
− the effect of ACI-24 on T cell activation
− the effects of ACI-24 on putative biomarkers of the progression of Alzheimer's disease like total tau and phosphorylated tau protein (phosphotau) and Aβ levels (Aβ1-42 and Aβ1-40) in blood and CSF
- the efficacy of ACI-24 on clinical/cognitive endpoints in patients with mild to moderate Alzheimer's disease
- the induction of immune response in serum and/or CSF including, but not limited to, anti-Aβ1-42 IgM titer in blood
- the induction of inflammatory cytokines in blood |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Probable AD according to NINCDS-ADRDA criteria
2. Florbetaben-PET scan at screening consistent with the presence of amyloid pathology
3. Mini-Mental Status Examination (MMSE) 18 – 28 points*
4. Age over 40 and less than 90 years**
5. Patients receiving a stable dose of an acetylcholinesterase inhibitor for at least 4 months prior to baseline
6. Patients cared for by a reliable spouse or caregiver to assure compliance, assist with clinical assessments and report safety issues
7. Women must be post-menopausal for at least one year, surgically sterilized or using reliable contraceptive measures
8. Patient who in the opinion of the investigator are able to understand and provide written informed consent
9. Patients and caregivers must be fluent in one of the languages of the study and able to comply with all study procedures
10. The patient is lucid and clear and oriented x4 and is able to provide their written informed
consent (applicable in Sweden only).
* For cohort 3 booster injection, the previous lower limit of 18 points for the MMSE will not be required but in all
cases patients must be oriented in time, place, person and current activities and able to give informed consent
in the opinion of the investigator in order to take part.
** For cohort 3 booster injection, no upper age limit applies.
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E.4 | Principal exclusion criteria |
1. Patients whose MRI scan within the last 6 months shows alternative pathology including severe vascular encephalopathy and/or more than 5 micro-hemorrhages.
2. Patients with other medical conditions which may influence cognitive performance e.g. Parkinson’s disease
3. Patients with any unstable medical condition (e.g. epilepsy, uncontrolled hypertension) which would hamper safety assessments
4. Patients receiving memantine within 3 months prior to baseline (for cohort 3 booster injection, memantine is allowed)
5. Patients receiving any anticoagulant drug
6. Patients with a history of hemorrhagic stroke
7. Patients with a history of non-hemorrhagic stroke or myocardial infarction within the last year
8. Patients with a history of major psychiatric disorder within the past 2 years
9. Patients with a history of inflammatory neurology disorders including meningoencephalitis
10.Clinically significant abnormalities of clinical hematology or biochemistry including, but not limited to, elevations greater than 1.5 times the upper limit of normal of SGOT, SGPT, or creatinine
11. Patients with a history of autoimmune disease
12. Patients with a history of cancer other than skin cancer within the past 5 years
13. Patients who have received any vaccine within the past 2 months before baseline
14. Patients who have previously received AD immune therapeutic agents or vaccines
15. Patients anticipated to receive any vaccination other than influenza vaccine during the study
16. Patients unable to undergo MRI examination for any reason, including metal implants contraindicated for MRI studies and claustrophobia
17. Patients with a positive HIV test at screening
18. Patients with positive syphilis serology
19. Women who are pregnant or planning to be pregnant, or who are lactating
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E.5 End points |
E.5.1 | Primary end point(s) |
- Safety and tolerability assessments: Adverse events; global assessment of tolerability; physical-, neurological- and psychiatric examination; vital signs; MRI imaging; electrocardiogram; routine hematology and biochemistry evaluation in blood- and urine; inflammatory markers in blood and cerebrospinal fluid
- Biological assessments: Immune response titer (serum anti-Aβ1-42 IgG titer)
- Efficacy assessments: Change from baseline over 1 year of total Cognitive score (Neuropsychological Test Battery) (for Step 2 only) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Safety and Tolerability: all time points
- Biological assessments: at multiple visits
- Efficacy assessments: NTB change from baseline at different visits |
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E.5.2 | Secondary end point(s) |
- Biological assessments: Brain Aβ assessed by PET amyloid imaging, whole brain and hippocampal volume assessed by MRI (for Step 2 only), T-cell activation assessed by ELISPOT analysis, Inflammatory cytokines titer in blood, Biomarkers in blood and CSF (e.g. total tau and phosphotau and Aβ levels (Aβ1-42 and Aβ1-40)), Immune response in blood/CSF (e.g. anti-Aβ1-42 IgM titer in blood and anti-Aβ1-42 IgG titer in blood/CSF), TLR4 expression, TLRs and NLRs expression
- Efficacy assessments: Global function [change from baseline in CDR (Clinical Dementia Rating Scale) sum of boxes], Activities of Daily Living (ADL) [change from baseline in Disability Assessment in Dementia (DAD)], other cognitive tests [change from baseline in ADAS-cog, MMSE, total NTB (including individual components, for Step 1 only)]; Behavior (change from baseline in NPI) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Biological assessments: at multiple visits
- Efficacy assessments: at multiple visits |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Adaptive design study with Phase I & II included |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The subjects will be treated for approximately 12 months (treatment period) and will enter a follow-up of 24 months (follow-up period). The end of the trial corresponds to the Last Patient Last Visit which is considered to be the last visit of the follow-up period.
The item E.8.9 below is valid for each subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |